Submissions for variant NM_001267550.2(TTN):c.53393del (p.Gly17798fs)

dbSNP: rs794729324

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184312	SCV000236937	pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	Has not been reported as associated with TTN-related disorders in the literature to the best of our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27535533, 35177841)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218440	SCV000271277	likely pathogenic	Primary dilated cardiomyopathy	2015-05-20	criteria provided, single submitter	clinical testing	The p.Gly15230fs variant in TTN has not been previously reported in individuals with cardiomyopathy or large population studies, though the ability of these pop ulation studies to accurately detect indels may be limited. This variant is pred icted to cause a frameshift, which alters the protein?s amino acid sequence begi nning at position 15230 and leads to a premature termination codon 18 amino acid s downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly associate d with DCM if they are located in the exons encoding for the A-band (Herman 2012 , Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Gly15230fs variant is located in A-band in the highly exp ressed exon 227. In summary, although additional studies are required to fully e stablish its clinical significance, the p.Gly15230fs variant is likely pathogeni c.
Invitae	RCV001047513	SCV001211476	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly17798Alafs*18) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (DCM) (Invitae). ClinVar contains an entry for this variant (Variation ID: 202451). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002426893	SCV002744580	likely pathogenic	Cardiovascular phenotype	2021-12-16	criteria provided, single submitter	clinical testing	The c.26198delG variant, located in coding exon 105 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 26198, causing a translational frameshift with a predicted alternate stop codon (p.G8733Afs*18). This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration, reported with alternative nomenclature c.45689delG, has been detected in a patient who suffered aborted sudden cardiac death and in her sibling with congestive heart failure (Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10:e001573). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic.